Progress toward developing more effective therapeutic regimens for chronic hepatitis C, including antiviral, immunomodulatory, or antifibrotic agents, has been stymied by two major technical deficiencies, both of which represent critical bottlenecks to drug discovery and evaluation. These include the absence of a cell culture system that is permissive for efficient replication of hepatitis C virus (HCV), and the lack of a readily available small animal model that mimics the pathogenesis of chronic hepatitis G in humans. The overarching aim of the work proposed in this application is to ameliorate the second of these technical deficiencies by the commercial development of transgenic mice that express hepatitis C proteins and/or viral RNAs in a liver-specific fashion and that either manifest hepatic pathology similar to that observed in human disease. The long range goal of these studies is to make available appropriately validated animal models that can be used in preclinical studies aimed at defining the therapeutic efficacy of novel interventions. In preliminary work, we have established several lines of transgenic mice that express either the complete open reading frame (ORF) of HCV or the segment of the ORF encoding the structural proteins under control of the liver-specific mouse albumin promoter/enhancer. In one relatively well characterized lineage (FL-N/35), we have observed enhanced hepatic steatosis in both males and females, and hepatocellular carcinoma in males over the age of 13 months. These histologic endpoints mimic findings in chronic hepatitis G, and provide substantial support for the utility of transgenic mice as models of hepatitis C in humans. In Specific Aim 1, we propose development of additional transgenic lineages, and further characterization of the phenotypes of mice expressing these HGV transgenes. In Specific Aim 2, we propose experiments aimed at elucidating the genetic and1or molecular requirements for steatosis and hepatocellular carcinoma in these mice. In Specific Aim 3, we propose the development of mice with inducible HGV transgenes, as the induction of HCV protein expression in immunologically mature mice will allow development of a model of the immunopathologically-mediated manifestations of hepatitis C. PROPOSED COMMERCIAL APPLICATIONS: The goal is to develop mouse models for use in preclinical studies of therapeutic interventions for hepatitis C.